Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma
Emilien Loeuillard, … , Haidong Dong, Sumera Ilyas
Emilien Loeuillard, … , Haidong Dong, Sumera Ilyas
Published July 14, 2020
Citation Information: J Clin Invest. 2020;130(10):5380-5396. https://doi.org/10.1172/JCI137110.
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Research Article Gastroenterology Oncology Article has an altmetric score of 26

Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma

Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. Desmoplastic malignancies, such as cholangiocarcinoma (CCA), have an abundant tumor immune microenvironment (TIME). However, to date, ICB monotherapy in such malignancies has been ineffective. Herein, we identify tumor-associated macrophages (TAMs) as the primary source of programmed death–ligand 1 (PD-L1) in human and murine CCA. In a murine model of CCA, recruited PD-L1+ TAMs facilitated CCA progression. However, TAM blockade failed to decrease tumor progression due to a compensatory emergence of granulocytic myeloid-derived suppressor cells (G-MDSCs) that mediated immune escape by impairing T cell response. Single-cell RNA sequencing (scRNA-Seq) of murine tumor G-MDSCs highlighted a unique ApoE G-MDSC subset enriched with TAM blockade; further analysis of a human scRNA-Seq data set demonstrated the presence of a similar G-MDSC subset in human CCA. Finally, dual inhibition of TAMs and G-MDSCs potentiated ICB. In summary, our findings highlight the therapeutic potential of coupling ICB with immunotherapies targeting immunosuppressive myeloid cells in CCA.

Authors

Emilien Loeuillard, Jingchun Yang, EeeLN Buckarma, Juan Wang, Yuanhang Liu, Caitlin Conboy, Kevin D. Pavelko, Ying Li, Daniel O’Brien, Chen Wang, Rondell P. Graham, Rory L. Smoot, Haidong Dong, Sumera Ilyas

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Figure 6

Single-cell transcriptomics demonstrates accumulation of unique G-MDSC subsets with TAM blockade.

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Single-cell transcriptomics demonstrates accumulation of unique G-MDSC s...
(A) Schematic depicting scRNA-Seq study of FACS-sorted G-MDSCs from control and anti-CSF1R–treated murine tumors. (B and C) Tumor growth of 28 days after orthotopic implantation of 1 × 106 SB (murine CCA) cells in WT mice. Mice were treated from day 14 to day 28 after implantation with control rat IgG isotype or anti-CSF1R (AFS98). (B) Cell clustering based on tSNE algorithm for WT mouse samples treated with control IgG or anti-CSF1R. Eight clusters were initially identified with high resolution (resolution = 0.5) based on a shared nearest neighbor clustering algorithm as implemented in Seurat. (C) Cell clusters with similar expression profiles were further combined with resultant 2 distinct cell clusters. Percentage of cells in cluster 0 was 98% for control sample and 86% for anti-CSF1R sample. P < 0.01, Fisher’s exact test. (D) Heatmap of gene expression profiles for selected top cluster-specific genes (n = 25 for cluster 0 and cluster 1). Expression values for each gene were Z scored across all cells. (E) Enrichment analysis for 40 signature human MDSC genes using AUCell in human CCA (n = 10). Significantly enriched cells are highlighted in red. (F) Enrichment analysis for 40 ApoE G-MDSC signature genes using AUCell in human CCA (n = 10). Significantly enriched cells are highlighted in red.